1. Malignant Hyperthermia Syndrome
Henry Rosenberg, M.D.
President, Malignant Hyperthermia Association of the United States (MHAUS)
Director, Department of Medical Education, Saint Barnabas Medical Center, Livingston, NJ

2. Malignant Hyperthermia (MH)- Essential Characteristics
An inherited disorder of skeletal muscle triggered in susceptibles (human or animal) in most instances by inhalation agents and/or succinylcholine, resulting in hypermetabolism, skeletal muscle damage, hyperthermia, and death if untreated.
Underlying physiologic mechanism – abnormal handling of intracellular calcium levels
MH is inherited as an autosomal dominant trait. This means that susceptibility is passed on to half the children from an affected adult.
Both males and females may be affected.

3. Trigger Agents for MH MH Trigger Agents
Potent Volatile Anesthetics (eg. halothane, sevoflurane, desflurane)
Succinylcholine
Not MH Triggers
Intravenous agents
Opioids
Non-depolarizing agents
Ketamine
Propofol
Anxiolytics
Only the potent gas anesthetics and the paralyzing agent succinylcholine trigger MH. Other drugs are safe.

4. Summary of Clinical Signs
In MH, anesthetic “trigger” drugs affect the metabolism of muscle through effects on cell calcium movements. Muscle damage, increased metabolism, increased acid content of the blood, abnormalities of electrolytes result. If not treated, death is likely.

5. Epidemiology of MH Incidence & Prevalence
Reported frequency of MH is 1 in 5,000 to
1 in 100,000 anesthetics
Reported from every country and ethnic group
Based on reports to MHAUS, there are about 600 cases of MH per year in the US.
MH “hotspots:” Wisconsin, Michigan, West Virginia
Other data show that up to 1 of every 3,000 people harbor the genetic change that predisposes to MH. This is the same order of magnitude as muscular dystrophy. Unfortunately, there are no outward signs to indicate who is at risk.

6. Epidemiology of MH (continued)
Mortality from MH
Per data from the North American MH Registry, of 291 events, 8 (2.7%) resulted in cardiac arrests and 4 (1.4%) resulted in death.
The median age in cases of cardiac arrest/death was 20 yr (range, 2-31 yr).
Factors associated with higher risk of poor outcome were muscular build and disseminated intravascular coagulation (DIC).
Increased risk of cardiac arrest/death was related to a longer time period between anesthetic induction and maximum end-tidal carbon dioxide.
Larach et al., 2008; Anesthesiology 108(4):

7. Epidemiology of MH (continued)
Mortality: Hospital vs. Ambulatory Settings
During the period January 2006 through May 2008, the MHAUS MH Hotline received:
503 calls from hospitals, 28 determined to be MH, with 2 deaths from MH (7% mortality)
44 calls from ambulatory settings,13 determined to be MH, with 3 deaths (21% mortality)
A fulminant MH episode occurring outside of the hospital setting is more likely to lead to a bad outcome as compared with an episode which originates in a hospital setting.
Studies are showing that when MH occurs in other than a hospital setting, the mortality is much higher. This may reflect lack of personnel, lack of coordination in moving the patient to the hospital, or other factors.

8. Clinical Signs of MH Specific Muscle Rigidity Increased CO2 Production
Rhabdomyolysis
Marked Temperature Elevation
Non-Specific
Tachycardia
Tachypnea
Acidosis (Respiratory/ Metabolic)
Hyperkalemia
The diagnosis of MH can be straightforward if all the signs occur rapidly, but the diagnosis can be subtle depending on the time of presentation of the signs of MH and the progression of the changes. In general, the first signs are an increase in exhalation of carbon dioxide, increase in heart rate and muscle rigidity (not always present). Several other conditions can lead to similar changes and the anesthesia provider needs to sort out the cause of the changes.

9. Spectrum of Clinical Presentations
Fulminant MH: muscle rigidity, high fever, increased HR shortly after induction of anesthesia
Masseter muscle rigidity (MMR): jaw muscle rigidity after succinylchoine may be an early sign of MH (see next slide)
Late onset MH: uncommon, may begin shortly after anesthesia finish time (usually within first hour)

10. Masseter Muscle Rigidity (MMR) and MH
Masseter muscle rigidity (MMR) may occur after succinylcholine
More common in children
Presages MH in 20-30% cases
All patients with MMR demonstrate elevated CK and often gross myoglobinuria
With muscle breakdown and CK > 20,000IU, the likelihood of MH is very high. Generalized rigidity not always present; if it occurs, MH is almost certain.
One of the sentinel signs of MH is jaw muscle rigidity after administering the paralyzing drug succinylcholine. This is more common in children than adults. When it occurs, clinical signs of MH may follow soon after. Even if no overt signs of MH occur, the patient needs to be observed for signs of muscle breakdown.

11. Muscle disorders and MH-Susceptibility
CCD (Central Core Disease) and MmD (Multiminicore Disease)– disorders of muscles used for movement. Often associated with mutations in the skeletal muscle ryanodine receptor gene (RYR1), the same gene associated with MH susceptibility.
Duchenne’s Muscular Dystrophy (DMD) –progressive, fatal muscle wasting disorder in males, due to absence of dystrophin protein. Cardiac problems are common.
Becker’s Muscular Dystrophy (BMD) – late onset muscular dystrophy in males, abnormal dystrophin protein, relatively normal life span.
Myotonias – defects in various skeletal muscle ion channels leading to impaired relaxation after voluntary muscle contraction.
Several muscle disorders have been associated with MH susceptibility. These are generally very uncommon conditions, but nevertheless patients with these conditions need to be treated as being MH susceptible.

12. Muscle disorders and MH-susceptibility
Patients with occult or known myopathies such as CCD, MmD, DMD, or BMD may have a higher risk for an MH or MH-like episode upon exposure to a triggering anesthetic agent. Such patients should be evaluated by a neurologist prior to providing treatment and/or diagnostic testing recommendations.
CCD, MmD associated with MH susceptibility.
Patients with Duchenne’s or Becker’s muscular dystrophies are at risk for hyperkalemic cardiac arrest with succinylcholine or other MH triggering agents (but this is NOT MH).
Individuals with any form of myotonia should not receive succinylcholine.
Hyperkalemia= high serum potassium levels. This occurs as a result of muscle membrane breakdown. In addition increased release of the muscle pigment , myoglobin , may occur and lead to kidney damage. 12

13. Treatment and Management of MH
Immediate Therapy
Discontinue inhalation agents, succinlycholine
Hyperventilate with 100% O2
Bicarbonate 1-2 mg/kg as needed
Get additional help
Dantrolene 2.5 mg/kg push, repeat PRN
Cool patient: gastic lavage, surface, wound
Treat arrhythmias – do not use calcium channel blockers
Arterial or venous blood gases
Electrolytes, coagulation studies
It is important to have a well defined and rehearsed plan for treatment of MH since many things have to be done simultaneously and treatment must be initiated immediately.

14. Dantrolene needs to be immediately available
Dantrolene needs to be immediately available. The drug needs to be reconstituted with bacteriostatic sterile water, 60ml/vial.
The average patient needs at least 9 vials to begin treatment and may need much more depending on the response to treatment. Dantrolene sodium for injection is available as Dantrium® IV from JHP Pharmaceuticals and as dantrolene sodium for injection from US WorldMeds.

15. Treatment and Management of MH
After Crisis is controlled
Give dantrolene 1 mg/kg every 4-6 hours for 24 – 48 hours
Monitor for recrudescence – rate is 25%
Follow electrolytes, blood gases, CK, core temperature, urine output and color, coagulation studies
Biochemical markers
Blood gases – esp pCO2, pH
Myoglobin levels in serum and urine
PT, PTT, INR, fibrin split products
Liver enzymes, BUN
Monitor for signs of myoglobinuria and rhabdomyolysis and institute therapy to prevent renal failure
Once the crisis is controlled, it is important to continue treatment with dantrolene and have the patient recover in an ICU since the syndrome can recur.

16. Prevention of Malignant Hyperthermia
Avoid MH trigger agents in MH susceptibles or those suspected of being susceptible
Preoperative personal/family history of anesthetic problems, neuromuscular disorders to identify those who may be MH-susceptible.
Temperature/endtidal CO2 monitoring during general anesthesia
Recognition of masseter muscle rigidity
Prompt investigation of unexplained tachycardia, hypercarbia, hyperthermia
Availability of Dantrolene
ORs should perform regular MH drills to be prepared.
Prompt recognition and treatment is crucial in managing MH. It should be emphasized that all patients undergoing general anesthesia for more than about 30 minutes should have their body temperature monitored.

17. Diagnostic Tests for MH-Susceptibility
Muscle Contracture Test: Caffeine Halothane Contracture Test (CHCT)
Gold Standard
Requires skeletal muscle biopsy from patient’s thigh to assess muscle contractile properties upon exposure to ryanodine receptor agonists (eg. caffeine, halothane).
Must be performed at the MH Muscle Biopsy Center.
Abnormally high levels of contractile force indicate MH susceptibility.
Sensitivity: close to 100% (false negatives are rare)
Specificity: ~80% (~20% false positives)
Diagnostic tests are most useful when making treatment decisions for surgical patients where there is a high level of
suspicion that the patient is susceptible to MH. Before any diagnostic testing is recommended, an evaluation of the patient’s susceptibility to MH should be completed using available medical data. Although the CHCT is the gold standard, it is an invasive, costly test.

18. Diagnostic Tests (Continued)
2. Genetic Testing (Ryanodine Receptor [RYR1] gene sequencing)
Involves isolation of DNA from patient sample (white blood, or muscle cells; or other tissue sample)
Primary genetic locus associated with MH susceptibility is the ryanodine receptor (RYR1) gene; a DNA variant in the gene is characterized as:
a. Unrelated polymorphism (no significant functional effect)
b. Causative mutation* (via functional studies)
c. Indeterminate (variant of unknown significance)
Presence of causative mutation* in RYR1 gene is diagnostic for MH susceptibility.
At this time, genetic testing is recommended as a confirmatory diagnostic measure for individuals known to be at high risk for
an MH event, as determined by their own or a first-degree (sibling, parent, offspring) family member’s clinical episode of MH
or positive muscle contracture test (caffeine-halothane contracture test).
*Currently 29 listed MH causative RYR1 mutations (see Additional ones expected to be added to panel in near future.

19. Diagnostic Tests (Continued)
2. Genetic Testing (Ryanodine Receptor [RYR1] gene sequencing)
At this point, not all proven MHS individuals have been found to harbor a causative mutation. The sensitivity of the genetic test depends upon several factors, including the population selected and the methodology of the testing utilized.
Once a causative mutation is found, family members can be tested for that specific causative mutation; if found, the individual is considered MHS and a muscle biopsy for contracture testing can be avoided.
It is hoped that , as more information is gathered about the genetics of MH, the DNA test will become more useful for diagnosing all patients as MH susceptible or not susceptible.
For more details about testing options for MH susceptibility, please refer to the MHAUS slide set available on our website at .

20. Preparation for the MH-Susceptible Patient
Shut/disable vaporizers
Older machines set O2 10L/min for 20 minutes
(through machine and ventilator)
OPTIONAL - Change carbon dioxide absorbent
Use non-trigger agents or local anesthesia
Monitor temperature and for early signs of MH
Have dantrolene available
Note: A separate, vapor-free anesthesia machine is not necessary.
The anesthesia machine needs to be purged of residual gases prior to use in a susceptible. The above recommendation will need to be modified for the newer generation of anesthesia machines. They may need a longer time for purging of the gases.
The practitioner should consult the manufacturer of the machine.

21. Management of the MH-susceptible Patient
MH-Susceptible individuals may undergo surgery – inpatient or outpatient; dantrolene is not necessary preoperatively
Avoid MH triggers (succinylcholine and potent inhalation agents)
Suggested regimen: Anxiolytic(e.g midazolam (ketamine permissible)  Propofol/opioid induction  Non-depolarizing relaxant Nitrous/narcotic/propofol  Reversal of muscle relaxant  Discharge after about 1.5 hours in the recovery room if all signs are stable
MH patients may be anesthetized with local anesthesia for example with spinal or epidural techniques, or using general anesthetics that are not MH triggers. An MH susceptible should not be deprived of general anesthesia if indicated by the surgery.

22. Evidence for Association between
Heat Stroke and MH
12 yr old boy with history of anesthesia-induced MH, develops fever, rigidity, rhabdomyolysis after soccer practice and dies. RYR-1 mutation detected in him and his relatives (Tobin et al., JAMA 2001; 286:169-70).
Experiments in genetically engineered mice provide evidence for mechanism underlying heat sensitivity in some MH patients - involves leakage of Ca2+ through the ryanodine receptor, coupled with the production of reactive nitrogen species which bind to the ryanodine receptor, making it more porous to Ca2+ leak when the muscle is heated. Ca2+ leak may lead to typical changes of MH and at same time lead to increased Ca2+ release (Durham et al., Cell Apr ; 133 (1): 53-65).
Although it is clear that the animal model for MH, certain swine, regularly develop awake signs of MH when stressed, this does not seem to occur with humans. However, there is evidence that the rare patient may develop muscle breakdown or even MH under certain conditions such as extreme heat and exercise. Much more work is necessary to clarify the relation to MH.

23. MH Resources
Malignant Hyperthermia Association of the United States (MHAUS)
Not-for-profit organization
Over 2,000 members including MH-susceptible patients and their family, medical professionals, corporations, and other interested individuals.
Mission of MHAUS - to promote optimum care and scientific understanding of MH and related disorders.
Provides the best medical and scientific advice available to patients and health care providers alike.
HOTLINE for Medical Professionals MH-HYPER - Available 24/7/365 to assist health providers in dealing with MH emergencies!
General Information: / MHAUS or
Website:

24. MH Resources (Continued)
The North American Malignant Hyperthermia Registry of MHAUS
Database which records detailed events surrounding MH episodes as well as correlation between clinical history, genetic, and biopsy test results
Patients and physicians can provide Registry with clinical history, thus the Registry acts as a service for patients/families and their health care professionals to communicate and store important medical histories relating to the risk for MH
Approved by the IRB of the University of Pittsburgh Medical Center
The Registry holds a certificate of confidentiality, reflective of its commitment to protect subject confidentiality
Director, Dr. Barbara Brandom
Phone: ; website: .

25. MHAUS Current Services and Products
MH Hotline
MH Expert Consult
MH Registry
Speaker’s Bureau
Patient Safety Products
Medical ID program and tag
MH Alert band and sticker kit
Family health history toolkit
Template letters for family and insurance companies
Safe/unsafe anesthetics pocket card
Educational and Training Materials
Website/FAQs
Brochures
Conferences
Slide shows, some with CME credits offered
Newsletter
Podcasts
MH Mock Drill Kit NEW
In-service kit (video/DVD with test for CEU credit)
MH procedural manual for hospital, ASC, and Office-based settings
Reference and Crisis Management Materials
MH Protocol as poster or pocket card
Transfer Guidelines for ASCs COMING SOON!
Crisis Management Sheets
Dantrolene Dosage Chart
MH Hotline Stickers

26. Suggested Resources/Reading
Brandom BW. Genetics of malignant hyperthermia. The Scientific World Journal 2006; 6:
Brandom BS. Ambulatory surgery and malignant hyperthermia. Curr Opin Anesthes 2009; 22:
Capacchione JF, Muldoon SM. The relationship between exertional heat illness, exertional rhabdomyolysis, and malignant hyperthermia. Anesth Analg 2009; 109:
Larach MG, Gronert GA, Allen GC, Brandom BW, Lehman EB. Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to Anesth Analg 2010; 110:
Larach MG, Brandom BW, Allen GC, Gronert GA, Lehman EB. Cardiac arrests and deaths associated with malignant hyperthermia in North America from 1987 to 2006: A report from the North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States. Anesthesiology 2008; 108:
Larach MG, Localio AR, Allen GC, Denborough MA, Ellis FR, Gronert GA, Kaplan RF, Muldoon SM, Nelson TE, Ording H, Rosenberg H, Waud BE, Wedel DJ. A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 1994; 80:

27. Suggested Resources/Reading (Continued)
MHAUS Guidelines. Testing for MH Susceptibility. Slide set available at
Muldoon S, Deuster P, Voelkel M, Capacchione J, Bunger R. Exertional heat illness, exertional rhabdomyolysis, and malignant hyperthermia: is there a link? Current Sports Medicine Reports; March/April 2008; 7(2):
Parness J, Lerman J, Stough RC. Malignant Hyperthermia. In: A Practice of Anesthesia for Infants and Children, 2009, Elsevier, Chapter 41, Fourth Edition (edition’s authors: Cote C, Lerman, J, Todres ID), pp
Rosenberg H, Davis M, James D, Pollock N, Stowell K. Malignant hyperthermia. Orphanet J Rare Dis 2007; 2:21
Rosenberg H, Sambuughin K, Dirksen RT. Malignant hyperthermia susceptibility. January 2010 in GeneReviews at GeneTests: Medical Genetics Information Resource [database online]. Copyright, University of Washington, Seattle, Available at <
Stowell K. Malignant hyperthermia: a pharmacogenetic disorder. Pharmacogenomics 2008; 9(11):

28. For a more in-depth, annotated slide presentation, including:
Historical landmarks in the discovery of MH
Common case presentations and errors in diagnosis
Helpful visual aides
Recent progress in MH research
….please refer to the slide set which can be ordered through the MHAUS website.